Spinal galanin systems play a role in the regulation of afferent processing that results in pain behavior after tissue and nerve injury. The spinal modulation appears to be mediated by activation of one or more of three cloned and expressed galanin receptors (Ga1R1,2,3) some of which are present in spinal cord. The focus of this proposal, characterizing these several aspects of galanin activity and pharmacology is underscored by five specific aims. Specific Aim 1: Systematically define the antinociceptive profile of intrathecal galanin and homologues in rats on models of acute nociceptive processing (thermal escape), post tissue injury pain states (formalin and carrageenan hyperalgesia), and in post nerve injury pain states (Chung tactile allodynia Vincristine evoked tactile allodynia). Specific Aim 2: Define the spinal receptor mediating the spinal action of galanin by examining the dose dependent activity of intrathecal galanin, homologues and fragments in rats treated with intrathecally delivered antisenses/mis-senses for the Gal 1, 2 and 3 receptors. Specific Aim 3: As galanin has a presynaptic locus in several systems and can block opening of calcium channels, determine if, in accord with its antinociceptive profile, these agonists modulate the evoked release of spinal glutamate and prostaglandin in vivo. Specific Aim 4 examine the behavioral characteristics and response to intrathecally delivered galanin agonists and antagonists in mice prepared to be over expressors of galanin. Specific aim 5 systematically characterize and compare displacement of I125 galanin binding in Gal-r specific expressing cell lines, suppression of adenylate cyclase and antinociceptive actions after intrathecal delivery of combrnatorially synthesized candidate families of peptidic (Galp fragments) and non-peptidic (galnon) molecules which are known to bind at the Ga1R sites. These studies will thus systematically define the actions of spinal galanin-ergic systems in regulating spinal nociceptive function. We believe the outcome of these studies will provide direct evidence for the role played by this spinal peptidergic system in pain and point to the development of novel anti-hyperpathic agents.